HPK1

BOSTON--( BUSINESS WIRE )-- Nimbus Therapeutics , LLC ("Nimbus Therapeutics" or "Nimbus"), a biotechnology company that designs and develops breakthrough medicines for patients through its powerful computational drug discovery engine, today announced the presentation of new clinical and translational data from its ongoing Phase 1/2 trial of NDI-101150, a novel, oral, potent and selective small-molecule hematopoietic progenitor kinase 1 (HPK1) inhibitor, for the treatment of advanced solid tumors. Results will be highlighted in two poster presentations at the Society for Immunotherapy of Cancer (SITC) 39 th Annual Meeting, taking place November 6-10, 2024 in Houston, Texas. The Phase 1/2 multicenter, open-label trial ( NCT05128487 ) is designed to assess NDI-101150 as a monotherapy (50-200 mg QD dose) and in combination with pembrolizumab (200 mg Q3W) in the treatment of adults with advanced solid tumors. The clinical results being presented at the SITC Annual Meeting include updated safety data from 53 patients in the dose escalation cohorts (n=41 on monotherapy, n=12 on combination therapy) and additional data from 35 patients in the dose expansion cohorts as well as updated efficacy data from 17 response-evaluable patients with renal cell carcinoma (RCC) who received NDI-101150 monotherapy. Results, as of August 12, 2024, showed: Safety Profile NDI-101150 was generally well-tolerated with immune-related adverse events supporting the proposed mechanism of action of HPK1 inhibition, which results in immune activation. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 14% of all patients exposed to NDI-101150 (n=88). The most common TRAEs were nausea, diarrhea, vomiting and fatigue. Efficacy and Target Engagement Treatment with NDI-101150 monotherapy resulted in objective responses in 18% (3/17) of response-evaluable RCC patients, including one complete response (CR) and two partial responses (PRs). A clinical benefit rate (CR + PR + stable disease [SD] ≥6 months) of 29% (5/17) and a disease control rate of 65% (11/17) were observed in response-evaluable RCC patients treated with NDI-101150 monotherapy. NDI-101150 effectively inhibited its target across multiple dose levels, providing strong pharmacodynamic evidence of the molecule's activity in patients. Supporting Mechanistic Evidence Analysis of tumor biopsies showed a more robust presence of immune cells post-treatment, with increased numbers of tumor-infiltrating lymphocytes and dendritic cells in the tumor microenvironment. Comprehensive gene expression profiling demonstrated broad activation of immune-related pathways, including enhanced interferon response and T cell activation signals. "These clinical results of NDI-101150 are highly encouraging, particularly in the context of renal cell carcinoma patients who have experienced disease progression on prior checkpoint inhibitors," said Nathalie Franchimont, M.D., Ph.D., Chief Medical Officer of Nimbus. "The objective responses and disease control rates seen thus far with NDI-101150 in heavily pretreated patients as well as the current safety profile support further evaluation of NDI-101150 in the clinic." "The clinical and translational data package being presented at SITC demonstrates both the therapeutic potential of NDI-101150 and the power of our computational drug discovery engine to design highly selective molecules against challenging targets like HPK1," said Jeb Keiper, M.S., MBA, Chief Executive Officer of Nimbus. "The monotherapy activity we observed is particularly noteworthy, as many second-generation immunotherapy compounds have struggled to show clinical benefit on their own. Together with its safety profile and the immune activation signals we've observed, these data support NDI-101150's potential as a novel oral non-checkpoint immunotherapy option for patients who need new treatment approaches beyond current checkpoint inhibitors." The abstracts are available in the Journal for ImmunoTherapy of Cancer (JITC) , the official journal of SITC, here and the details of the poster presentations are as follows: Title: Ongoing Phase 1/2 Trial of the HPK1 Inhibitor NDI-101150 as Monotherapy and in Combination with Pembrolizumab: Clinical Safety Update and Renal Cell Carcinoma (RCC) Efficacy Analysis Lead Author: David Sommerhalder, M.D., Director of Clinical Research, NEXT Oncology Date: Saturday, November 9, 2024 Time: 9:00 a.m. – 8:30 p.m. CST Category: Clinical Trials in Progress Abstract Number: 682 Title: Tumor Immune Microenvironment Characterization from Pre- and Post-Dose Tumors Collected from a Phase 1/2 Study of NDI-101150, a Hematopoietic Progenitor Kinase 1 (HPK1) inhibitor Lead Author: Scott Daigle, Senior Director, Translational Medicine, Nimbus Therapeutics Date: Friday, November 8, 2024 Time: 9:00 a.m. – 7:00 p.m. CST Category: Biomarkers, Immune Monitoring and Novel Technologies Abstract Number: 83 About Nimbus Therapeutics Nimbus Therapeutics is a clinical-stage, structure-based drug discovery company developing novel small molecule medicines designed to act against well-validated but difficult-to-drug targets implicated in multiple human diseases. The company advances promising research based on a unique strategy that combines leading-edge computational technologies with a tailored array of machine learning-based predictive modeling approaches. Nimbus' pipeline includes a clinical-stage HPK1 inhibitor for the treatment of cancer (NCT05128487), as well as a diverse portfolio of preclinical programs focused on cancer, including a WRN program for MSI-H cancers, autoimmune conditions, and metabolic diseases. The company is headquartered in Boston, Mass. To learn more about Nimbus, please visit www.nimbustx.com .

— New development candidate, NTX-452, a non-covalent WRN inhibitor, demonstrated significant tumor regression and complete responses at low oral doses in MSI-H tumor models refractory to immunotherapy and chemotherapy — — Company plans to initiate clinical trial of NTX-452 in first half of 2025 — BOSTON, MA, USA I October 23, 2024 I Nimbus Therapeutics , LLC (“Nimbus Therapeutics” or “Nimbus”), a biotechnology company that designs and develops breakthrough medicines for patients through its powerful computational drug discovery engine, announced that it is presenting preclinical data on its new development candidate, NTX-452, a novel Werner syndrome helicase (WRN) inhibitor, at the 36 th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, taking place October 23-25, 2024 in Barcelona, Spain. WRN is a helicase required for DNA replication and DNA repair and is a validated target for tumors with microsatellite instability (MSI). MSI is a phenotypic consequence of defective mismatch repair (dMMR) and occurs in various tumor types, including colorectal, gastric and endometrial cancers. Inhibition of WRN activity has the potential to induce synthetic lethality in MSI-high (MSI-H) tumors. Using a structure-based drug design approach, Nimbus developed highly potent and selective covalent and non-covalent inhibitors of WRN, and has selected a novel non-covalent inhibitor, NTX-452, as the clinical candidate. In a poster (abstract #356) titled “Preclinical Characterization of NTX-452, a Potent, Selective and Highly Efficacious WRN Inhibitor for the Treatment of MSI-H Tumors,” Nimbus is presenting new data from preclinical assays and several tumor models that support the potential of the company’s non-covalent WRN inhibitor as a treatment for MSI-H tumors. Key findings from the preclinical studies include: “These compelling preclinical results for NTX-452 further highlight the significant potential of our WRN inhibitor as a promising therapeutic approach for patients with MSI-H tumors, many of whom fail to respond to or eventually relapse with current standard of care therapies including immune checkpoint inhibitors,” said Peter Tummino, Ph.D., Chief Scientific Officer of Nimbus. “Our novel non-covalent approach to WRN inhibition, coupled with the robust efficacy demonstrated across diverse tumor types and treatment settings, positions our program for potential best-in-class status. We are particularly encouraged by the low doses required to achieve robust anti-tumor activity in preclinical models, which may translate to an improved benefit-risk profile in the clinic.” The preclinical profile of NTX-452 suggests several potential advantages in the treatment of MSI-H tumors, including: Nimbus is advancing NTX-452 with plans to enter the clinic in the first half of 2025. About Nimbus Therapeutics Nimbus Therapeutics is a clinical-stage, structure-based drug discovery company developing novel small molecule medicines designed to act against well-validated but difficult-to-drug targets implicated in multiple human diseases. The company advances promising research based on a unique strategy that combines leading-edge computational technologies with a tailored array of machine learning-based predictive modeling approaches. Nimbus’ pipeline includes a clinical-stage HPK1 inhibitor for the treatment of cancer (NCT05128487), as well as a diverse portfolio of preclinical programs focused on cancer, including the WRN program, autoimmune conditions, and metabolic diseases. The company is headquartered in Boston, Mass. To learn more about Nimbus, please visit www.nimbustx.com . SOURCE: Nimbus Therapeutics

-- New development candidate, NTX-452, a non-covalent WRN inhibitor, demonstrated significant tumor regression and complete responses at low oral doses in MSI-H tumor models refractory to immunotherapy and chemotherapy -- -- Company plans to initiate clinical trial of NTX-452 in first half of 2025 -- BOSTON--(BUSINESS WIRE)-- Nimbus Therapeutics , LLC (“Nimbus Therapeutics” or “Nimbus”), a biotechnology company that designs and develops breakthrough medicines for patients through its powerful computational drug discovery engine, announced that it is presenting preclinical data on its new development candidate, NTX-452, a novel Werner syndrome helicase (WRN) inhibitor, at the 36 th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, taking place October 23-25, 2024 in Barcelona, Spain. WRN is a helicase required for DNA replication and DNA repair and is a validated target for tumors with microsatellite instability (MSI). MSI is a phenotypic consequence of defective mismatch repair (dMMR) and occurs in various tumor types, including colorectal, gastric and endometrial cancers. Inhibition of WRN activity has the potential to induce synthetic lethality in MSI-high (MSI-H) tumors. Using a structure-based drug design approach, Nimbus developed highly potent and selective covalent and non-covalent inhibitors of WRN, and has selected a novel non-covalent inhibitor, NTX-452, as the clinical candidate. In a poster (abstract #356) titled “Preclinical Characterization of NTX-452, a Potent, Selective and Highly Efficacious WRN Inhibitor for the Treatment of MSI-H Tumors,” Nimbus is presenting new data from preclinical assays and several tumor models that support the potential of the company’s non-covalent WRN inhibitor as a treatment for MSI-H tumors. Key findings from the preclinical studies include: NTX-452 demonstrated potent and selective inhibition of WRN activity with favorable drug-like properties. The compound showed synthetic lethality in MSI-H tumor cells, triggering a DNA damage response that suppressed cell viability and promoted cell death. Treatment with NTX-452 at low doses in vivo exhibited a robust pharmacodynamic response, resulting in tumor regression across multiple MSI-H cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) tumor models, including established models for colorectal, gastric and endometrial cancers. Significant tumor regression and complete responses were observed at low oral doses in MSI-H models refractory to immunotherapy and chemotherapy. “These compelling preclinical results for NTX-452 further highlight the significant potential of our WRN inhibitor as a promising therapeutic approach for patients with MSI-H tumors, many of whom fail to respond to or eventually relapse with current standard of care therapies including immune checkpoint inhibitors,” said Peter Tummino, Ph.D., Chief Scientific Officer of Nimbus. “Our novel non-covalent approach to WRN inhibition, coupled with the robust efficacy demonstrated across diverse tumor types and treatment settings, positions our program for potential best-in-class status. We are particularly encouraged by the low doses required to achieve robust anti-tumor activity in preclinical models, which may translate to an improved benefit-risk pro the clinic.” The preclinical pro NTX-452 suggests several potential advantages in the treatment of MSI-H tumors, including: The non-covalent mechanism may offer more durable on-target activity, and a greater safety window compared to covalent inhibitors. High potency and favorable pharmacokinetic properties indicate the potential for target levels of efficacy at lower doses. Broad efficacy across treatment-naïve, chemotherapy-pretreated, and immunotherapy-pretreated models suggests potential utility in both early-stage and advanced disease settings. Activity in multiple MSI-H tumor types, including those with diverse genetic alterations, indicates potential broad applicability across dMMR/MSI-H cancers. Nimbus is advancing NTX-452 with plans to enter the clinic in the first half of 2025. About Nimbus Therapeutics Nimbus Therapeutics is a clinical-stage, structure-based drug discovery company developing novel small molecule medicines designed to act against well-validated but difficult-to-drug targets implicated in multiple human diseases. The company advances promising research based on a unique strategy that combines leading-edge computational technologies with a tailored array of machine learning-based predictive modeling approaches. Nimbus’ pipeline includes a clinical-stage HPK1 inhibitor for the treatment of cancer (NCT05128487), as well as a diverse portfolio of preclinical programs focused on cancer, including the WRN program, autoimmune conditions, and metabolic diseases. The company is headquartered in Boston, Mass. To learn more about Nimbus, please visit . Contacts Media Cindy Fung, PhD Nimbus Therapeutics cindy.fung@nimbustx.com